Caspofungin (CAS 162808-62-0) is the first of a new class of semi-synthetic antifungal agents belonging to the class of echinocandins. It may be represented by the formula I

Caspofungin is commonly prepared by synthetic derivatisation of pneumocandin B0 which is obtained by fermentation of the fungus Glarea lozoyensis. The antifungal activity of caspofungin is due to its inhibition of the biosynthesis of β-(1,3)-D-glucan, an integral component of the fungal cell wall. It is used for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies, as well as empirical therapy for presumed fungal infections in febrile, neutropenic patients.
Caspofungin as a compound is claimed in the patent U.S. Pat. No. 5,378,804 issued to Merck & Co.
U.S. Pat. No. 5,952,300 discloses a composition for treating and/or preventing fungal infections comprising caspofungin and the pharmaceutically active salt thereof, a pharmaceutically active amount of an acetate buffer and a pharmaceutically acceptable amount of excipients such as a sucrose/mannitol mixture to form a lyophilized cake.
A lyophilized caspofungin product is available on the marketed as its diacetate salt by Merck & Co., under the trade name Cancidas® (RLD product). Cancidas® contains in addition to the active ingredient caspofungin diacetate, acetic acid, sodium hydroxide, sucrose and mannitol. Before administration to a patient, the lyophilized product is reconstituted by adding a diluent and the desired amount of the diluted mixture is transferred to infusion bag to be administered to the patient in need thereof.
A well known problem with caspofungin compositions prepared for reconstitution prior to administration to the patient, is that the compound is highly unstable resulting in the formation of various degradation products such as e.g. hydrolysis products (impurity B) and dimerization products (impurity C). There will also be impurities present in the composition being formed during the fermentation of the starting material and which have passed along through the synthesis of caspofungin. The main impurity originating from the fermentation is the serine analogue of caspofungin having the formula as shown in WO 2009/158034
In addition to the above mentioned degradation impurities and impurities formed during preparation of known caspofungin compositions, further non-characterised impurities are also present. The mechanisms behind the formation of the impurities are not fully understood. However, it is known that the buffer system used when preparing the composition may increase the degradation product formation during preparation and storage. In U.S. Pat. No. 5,952,300 it is, for example, stated that the use of tartrate buffer resulted in undesired degradation products. The solution to the degradation problem according to the teaching of U.S. Pat. No. 5,952,300 is the use of an acetate buffer.
Various other strategies are also known to avoid degradation and improve the stability of caspofungin compositions. For example, in WO 2009/002481, a lyophilized caspofungin composition comprising in addition to caspofungin diacetate and an acetate buffer, one or more non-reducing sugars such as trehalose, sucrose, raffinose, or sorbitol or combinations thereof is disclosed.
In WO 2008/012310, a caspofungin composition is disclosed comprising, in addition to a pharmaceutically acceptable salt of caspofungin and excipients, only very low levels of a buffering agent, or which is free of a buffering agent.
Although various solutions to the impurity problem are suggested in the prior art, there is still a need for a caspofungin composition with improved stability in respect of the formation of impurities during storage.